Table 1 Making a Difference: Taking the Challenges of the Clinic Back to the Laboratory

When Michael Dyer, PhD, first arrived at St. Jude as a junior faculty member nine years ago, he was the head of a basic developmental neurobiology research laboratory. One day, while deciding how to set up his laboratory space, there was a knock at his door. Two clinicians who treat retinoblastoma patients asked him to spend some time with them in the clinic. He realized that after spending five years at a major medical center and studying normal eye development and genetic mutations of the eye, he had never once met a clinician, patient, or patient’s family. He eagerly accepted the opportunity.

Dyer knew that Rb gene mutations cause retinoblastoma, a rare childhood cancer with only 300 cases per year in the United States. But when he asked the clinicians if the tens of thousands of papers available on PubMed on the Rb gene and pathway had any impact on how patients are treated, they replied that they had no impact whatsoever. This surprising response led him to change the direction of his career and the research direction of his laboratory.

To Dyer, the reason these basic research papers had not been translated into new therapies was obvious: there was a lack of good animal models for this disease. Researchers had tried to develop a retinoblastoma model by deleting the Rb gene from the mouse genome, but the manipulation did not cause the mouse to develop retinoblastoma. Unbeknownst to them at the time, another protein, p107, is able to compensate for Rb in the mouse. When both Rb and p107 are deleted from the mouse genome, retinoblastoma develops in about 50 percent of the animals. Using this model, he was able to test different therapeutics against the disease. In doing so, Dyer applied what he learned from his clinical colleagues about the actual course of treatment in patients (i.e., clinical reality) and tested combinations of broad-spectrum systemic 45 chemotherapeutics in a similar manner in his mice. After going through eight different combinations of drugs and comparing them to the current standard of care, Dyer and his colleagues found a combination that seemed to be better than what children currently were receiving. St. Jude started a new five-year clinical trial based on those data. Although going from nothing to a new clinical trial in about 18 months was satisfying, Dyer hoped to do better.

He wanted to develop a more targeted chemotherapy that could be delivered locally to the eye and result in fewer side effects.

Searching for a drug target, Dyer’s team discovered that patients with retinoblastoma have increased levels of MDMX, which sequesters p53, a tumor suppressor, and leads to cell proliferation and tumor development. MDMX is amplified in 65 percent of patients and epigenetically turned on in the rest.

Now having a target to go after, Dyer and colleagues developed a model in which the MDMX gene was conditionally over expressed in the mice that develop retinoblastoma. This resulted in a much more aggressive disease in these animals—providing a new model to test chemotherapeutics. Not wanting to rely solely on a genetic model, they also developed a “xenographic” mouse model in which human tumor cells are transplanted to an eye of an immunocompromised mouse. This results in virtually 100 percent engraftment with tumors expressing high levels of MDMX. Collaborations with his chemical biology colleagues, who were able to synthesize an MDMX inhibitor, and clinicians, who provided medical information and tumor specimens, enabled Dyer to begin a preclinical trial focused on inhibiting MDMX.

Dyer believes that the process by which basic investigators can translate their discoveries into clinical applications could be emulated at most major medical or academic research centers. The building blocks important for driving translation, such as strong basic science departments, animal research facilities, pharmacology and pathology departments, and clinical trial support are already in place. He also noted that some translational work can be done with relatively few resources if one acts creatively. He received no support from St. Jude to fund these studies directly. Rather, Dyer built on a one-year pilot grant of $50,000 and cobbled the rest together through other sources.

The challenge, he said, is changing the culture. Emphasizing the value of translational research to both basic and clinical scientists, encouraging communications between basic and clinical scientists, mentoring, and understanding the clinical reality of disease progression and therapeutic interventions are all important for increasing participation in translational research and ultimately improving human health.